Methiopropamine

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Methiopropamine
Methiopropamine-2d-skeletal.svg
Methiopropamine.png
Clinical data
ATC code N06AA
Legal status
Legal status
  • DE: Anlage I (Controlled)
  • UK: Temporary Class Drug
  • Illegal in China, Finland, Florida
Identifiers
Synonyms MPA; Methiopropamine; Methedrene; Syndrax
CAS Number 801156-47-8 N
7464-94-0 (hydrochloride)
PubChem (CID) 436156
ChemSpider 385727 YesY
UNII 64ON2ETH7I N
Chemical and physical data
Formula C8H13NS
Molar mass 155.261 g/mol
3D model (Jmol) Interactive image
 NYesY (what is this?)  (verify)

Methiopropamine (MPA) is a thiophene ring-based structural analog of methamphetamine originally reported in 1942.[1] Chemically it is not a phenethylamine or amphetamine and is not their functional analog either. It originally appeared for public sale in the UK in December 2010 as a "research chemical" or "legal high", recently branded as Blow.[2] It has limited popularity as a recreational stimulant.[3][unreliable source?]

Pharmacology[edit]

Methiopropamine functions as a selective norepinephrine-dopamine reuptake inhibitor that is approximately 1.85 times more selective for norepinephrine than dopamine. It is approximately one third as potent as dextroamphetamine as a norepinephrine reuptake inhibitor and one fifth as much as a dopamine reuptake inhibitor. It displays negligible activity as a serotonin reuptake inhibitor.[4][5]

Metabolism[edit]

Methiopropamine metabolism is somewhat similar to methamphetamine. Hydroxylation, demethylation and deamination are in common. Formation of thiophene S-oxide is different, as is the end product which will probably be (substituted) thiophene-2-carboxylic acid. It is then excreted in urine. Compounds on red are inactive.

For N-alkyl amphetamines, deamination and N-dealkylation are the major elimination pathways and renal excretion is a minor one.[6] Methiopropamine is metabolized into active thiopropamine, 4-hydroxymethiopropamine and thiophene S-oxides.[7][8] These N-demethylated metabolites are further deaminated by the cytochrome P450 enzyme CYP2C19 in the liver transforming them into inactive 1-(thiophen-2-yl)-2-propan-2-one which can be seen as a phenylacetone derivative.[9][10]

Thiophene-2-carboxylic acid is the final major metabolic product. It is very hydrophilic and is excreted in urine. Methiopropamine and especially thiopropamine are also excreted renally, unchanged.

Synthesis[edit]

There is a four-step synthesis of methiopropamine. It begins with (thiophen-2-yl)magnesium bromide, which is reacted with propylene oxide, yielding 1-(thiophen-2-yl)-2-hydroxypropane which is reacted with phosphorus tribromide, yielding 1-(thiophen-2-yl)-2-bromopropane which is finally reacted with methylamine, yielding 1-(thiophen-2-yl)-2-methylaminopropane.[11]

Four-step synthesis of racemic methiopropamine from (thiophen-2-yl)magnesium bromide.

Legal status[edit]

China[edit]

As of October 2015 MPA is a controlled substance in China.[12]

Finland[edit]

Methiopropamine is illegal in Finland.[citation needed]

Germany[edit]

Methiopropamine is explicitly illegal in Germany.

United Kingdom[edit]

Following the ban on ethylphenidate authorities noticed an increase in methiopropamine use by injecting users. The ACMD suggested it be banned on 18 November 2015[13] as it had similar effects to ethylphenidate. The government enacted a temporary drug control order a week later which came into force on 27 November 2015.[14] Though ordinarily the TCDO would only last 1 year, the ACMD reported that since its invocation prevalence of MPA had significantly decreased, and that it had been challenging to collect information about the drug. As a result of this, they requested that the TCDO be extended a further year.[15]

United States[edit]

Methiopropamine is not scheduled at the federal level in the United States.[16]

Florida[edit]

Methiopropamine is a Schedule I controlled substance in the state of Florida making it illegal to buy, sell, or possess in Florida.[17]

See also[edit]

References[edit]

  1. ^ Blicke, F. F.; Burckhalter, J. H. (March 1942). "α-Thienylaminoalkanes". Journal of the American Chemical Society. 64 (3): 477–80. doi:10.1021/ja01255a001. 
  2. ^ Angelov, D; O'Brien, J; Kavanagh, P (March 2013). "The syntheses of 1-(2-thienyl)-2-(methylamino) propane (methiopropamine) and its 3-thienyl isomer for use as reference standards". Drug testing and analysis. 5 (3): 145–9. doi:10.1002/dta.298. PMID 21770051. 
  3. ^ Methiopropamine Thread at UKChemicalResearch.org
  4. ^ Iversen, L.; Gibbons, S.; Treble, R.; Setola, V.; Huang, X. P.; Roth, B. L. (January 2013). "Neurochemical profiles of some novel psychoactive substances". European Journal of Pharmacology. 700 (1-3): 147–151. doi:10.1016/j.ejphar.2012.12.006. PMC 3582025Freely accessible. PMID 23261499. 
  5. ^ Hyung Shin Yoon; Wen Ting Cai; Young Hun Lee; Kyung Tae Park; Yong Sup Lee; Jeong-Hoon Kim (2016). "The expression of methiopropamine-induced locomotor sensitization requires dopamine D2, but not D1, receptor activation in the rat". Behavioural Brain Research. 311: 403–7. doi:10.1016/j.bbr.2016.05.060. PMID 27265782. 
  6. ^ Vree, T.B.; Gorgels, J.P.M.C.; Muskens, A.Th.J.M.; Van Rossum, J.M. (September 1971). "Deuterium isotope effects in the metabolism of n-alkylsubstituted amphetamines in man". Clinica Chimica Acta. 34 (2): 333–44. doi:10.1016/0009-8981(71)90187-2. PMID 5113570. 
  7. ^ Treiber, Alexander; Dansette, Patrick M.; El Amri, Hamid; Girault, Jean-Pierre; Ginderow, Daria; Mornon, Jean-Paul; Mansuy, Daniel (1997). "Chemical and Biological Oxidation of Thiophene:  Preparation and Complete Characterization of Thiophene S-Oxide Dimers and Evidence for Thiophene S-Oxide as an Intermediate in Thiophene Metabolism in Vivo and in Vitro". Journal of the American Chemical Society. 119 (7): 1565–71. doi:10.1021/ja962466g. 
  8. ^ Dansette, P.M.; Thang, Do Cao; Mansuy, H. El Amri D.; Mansuy, D (August 1992). "Evidence for thiophene-s-oxide as a primary reactive metabolite of thiophene in vivo: Formation of a dihydrothiophene sulfoxide mercapturic acid". Biochemical and Biophysical Research Communications. 186 (3): 1624–30. doi:10.1016/S0006-291X(05)81594-3. PMID 1510686. 
  9. ^ Yamada, Hideyuki; Shiiyama, Sachiko; Soejimaohkuma, Toyomi; Honda, Shin-Ichiro; Kumagai, Yoshito; Cho, Arthur K.; Oguri, Kazuta; Yoshimura, Hidetoshi (February 1997). "Deamination of amphetamines by cytochromes P450: Studies on substrate specificity and regioselectivity with microsomes and purified CYP2C subfamily isozymes". The Journal of Toxicological Sciences. 22 (1): 65–73. doi:10.2131/jts.22.65. PMID 9076658. 
  10. ^ Welter, J.; Meyer, M.R.; Wolf, E.U.; Weinmann, W.; Kavanaugh, P.; Maurer, H.H. (April 2013). "2-methiopropamine, a thiophene analogue of methamphetamine: studies on its metabolism and detectability in the rat and human using GC-MS and LC-(HR)-MS techniques". Analytical and Bioanalytical Chemistry. 405 (10): 3125–3135. doi:10.1007/s00216-013-6741-4. PMID 23361230. 
  11. ^ Casale, John F.; Hays, Patrick A. (2011). "Methiopropamine: An Analytical Profile" (PDF). Microgram Journal. 8 (2): 53–7. 
  12. ^ "关于印发《非药用类麻醉药品和精神药品列管办法》的通知" (in Chinese). China Food and Drug Administration. 27 September 2015. Retrieved 1 October 2015. 
  13. ^ Advisory Council on the Misuse of Drugs (25 November 2015). "Methiopropamine (MPA): A review of the evidence of use and harm" (pdf). UK Home Office. Retrieved 27 November 2015. 
  14. ^ "The Misuse of Drugs Act 1971 (Temporary Class Drug) (No. 3) Order 2015". UK Government. 23 November 2015. 
  15. ^ "Re: Temporary Class Drug Order on methiopropamine". 2016. Retrieved 2016-11-28. 
  16. ^ 21 CFR — SCHEDULES OF CONTROLLED SUBSTANCES §1308.11 Schedule I.
  17. ^ Florida Statutes - Chapter 893 - DRUG ABUSE PREVENTION AND CONTROL
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